Individualized dosing parameters for tacrolimus in the presence of voriconazole: a real-world PopPK study.

Objectives: Significant increase in tacrolimus exposure was observed during co-administration with voriconazole, and no population pharmacokinetic model exists for tacrolimus in renal transplant recipients receiving voriconazole. To achieve target tacrolimus concentrations, an optimal dosage regimen is required. This study aims to develop individualized dosing parameters through population pharmacokinetic analysis and simulate tacrolimus concentrations under different dosage regimens. Methods: We conducted a retrospective study of renal transplant recipients who were hospitalized at the Second Xiangya Hospital of Central South University between January 2016 and March 2021. Subsequently, pharmacokinetic analysis and Monte Carlo simulation were employed for further analysis. Results: Nineteen eligible patients receiving tacrolimus and voriconazole co-therapy were included in the study. We collected 167 blood samples and developed a one-compartment model with first-order absorption and elimination to describe the pharmacokinetic properties of tacrolimus. The final typical values for tacrolimus elimination rate constant (Ka), apparent volume of distribution (V/F), and apparent oral clearance (CL/F) were 8.39 h-1, 2690 L, and 42.87 L/h, respectively. Key covariates in the final model included voriconazole concentration and serum creatinine. Patients with higher voriconazole concentration had lower tacrolimus CL/F and V/F. In addition, higher serum creatinine levels were associated with lower tacrolimus CL/F. Conclusion: Our findings suggest that clinicians can predict tacrolimus concentration and estimate optimal tacrolimus dosage based on voriconazole concentration and serum creatinine. The effect of voriconazole concentration on tacrolimus concentration was more significant than serum creatinine. These findings may inform clinical decision-making in the management of tacrolimus and voriconazole therapy in solid organ transplant recipients.

Factors affecting the effectiveness and safety of polymyxin B in the treatment of Gram-negative bacterial infections: A meta-analysis of 96 articles.

PURPOSE: Polymyxin B, with its unique structure and mechanism of action, has emerged as a key therapeutic agent against Gram-negative bacteria. The study aims to explore potential factors to influence its effectiveness and safety. METHODS: A model-based meta-analysis of 96 articles was conducted, focusing on factors like dosage, bacterial species, and combined antibiotic therapy. The analysis evaluated mortality rates and incidence rate of renal dysfunction, also employing parametric survival models to assess 30-d survival rates. RESULTS: In the study involving 96 articles and 9716 patients, polymyxin B's daily dose showed minimal effect on overall mortality, with high-dose group mortality at 33.57% (95% confidence intervals [CI]: 29.15-38.00) compared to the low-dose group at 35.44% (95% CI: 28.99-41.88), P = 0.64. Mortality significantly varied by bacterial species, with Pseudomonas aeruginosa infections at 58.50% (95% CI: 55.42-63.58). Monotherapy exhibited the highest mortality at 40.25% (95% CI: 34.75-45.76), P < 0.01. Renal dysfunction was more common in high-dose patients at 29.75% (95% CI: 28.52-30.98), with no significant difference across antibiotic regimens, P = 0.54. The 30-d overall survival rate for monotherapy therapy was 63.6% (95% CI: 59.3-67.5) and 70.2% (95% CI: 64.4-76.2) for association therapy with ß-lactam drugs. CONCLUSIONS: The dosage of polymyxin B does not significantly change death rates, but its effectiveness varies based on the bacterial infection. Certain bacteria like P. aeruginosa are associated with higher mortality. Combining polymyxin B with other antibiotics, especially ß-lactam drugs, improves survival rates. Side effects depend on the dose, with lower doses being safer. These findings emphasize the importance of customizing treatment to balance effectiveness and safety.

Pre-treatment risk predictors of valproic acid-induced dyslipidemia in pediatric patients with epilepsy.

Background: Valproic acid (VPA) stands as one of the most frequently prescribed medications in children with newly diagnosed epilepsy. Despite its infrequent adverse effects within therapeutic range, prolonged VPA usage may result in metabolic disturbances including insulin resistance and dyslipidemia. These metabolic dysregulations in childhood are notably linked to heightened cardiovascular risk in adulthood. Therefore, identification and effective management of dyslipidemia in children hold paramount significance. Methods: In this retrospective cohort study, we explored the potential associations between physiological factors, medication situation, biochemical parameters before the first dose of VPA (baseline) and VPA-induced dyslipidemia (VID) in pediatric patients. Binary logistic regression was utilized to construct a predictive model for blood lipid disorders, aiming to identify independent pre-treatment risk factors. Additionally, The Receiver Operating Characteristic (ROC) curve was used to evaluate the performance of the model. Results: Through binary logistic regression analysis, we identified for the first time that direct bilirubin (DBIL) (odds ratios (OR) = 0.511, p = 0.01), duration of medication (OR = 0.357, p = 0.009), serum albumin (ALB) (OR = 0.913, p = 0.043), BMI (OR = 1.140, p = 0.045), and aspartate aminotransferase (AST) (OR = 1.038, p = 0.026) at baseline were independent risk factors for VID in pediatric patients with epilepsy. Notably, the predictive ability of DBIL (AUC = 0.690, p < 0.0001) surpassed that of other individual factors. Furthermore, when combined into a predictive model, incorporating all five risk factors, the predictive capacity significantly increased (AUC = 0.777, p < 0.0001), enabling the forecast of 77.7% of dyslipidemia events. Conclusion: DBIL emerges as the most potent predictor, and in conjunction with the other four factors, can effectively forecast VID in pediatric patients with epilepsy. This insight can guide the formulation of individualized strategies for the clinical administration of VPA in children.

Association of Preablation Plasma Corin Levels With Atrial Fibrillation Recurrence After Catheter Ablation: A Prospective Observational Study.

BACKGROUND: We assessed the impact of pre- and postprocedural plasma corin levels on the recurrence of atrial fibrillation (AF) after catheter ablation (CA). METHODS AND RESULTS: This prospective, single-center, observational study included patients undergoing their first CA of AF. Corin was measured before and 1 day after CA. The primary end point was recurrent AF between 3 and 12 months after ablation. From April 2019 through May 2021, we analyzed 616 patients with AF (59.09% men) with a mean age of 62.86±9.42 years. Overall, 153 patients (24.84%) experienced recurrent AF. In the recurrence group, the pre- and postprocedure corin concentrations were 539.14 (329.24-702.08) and 607.37 (364.50-753.80) pg/mL, respectively, which were significantly higher than the nonrecurrence group's respective concentrations of 369.05 (186.36-489.28) and 489.12 (315.66-629.05) pg/mL (both P<0.0001). A multivariate Cox regression analysis with confounders found that elevated preablation corin levels were significantly associated with an increased risk of AF recurrence after CA. Receiver operating characteristic curve analysis identified that a preablation corin threshold of >494.85 pg/mL predicted AF recurrence at 1 year. An increase of 1 SD in corin concentrations before CA (264.94 pg/mL) increased the risk of recurrent AF by 54.3% after adjusting for confounding variables (hazard ratio, 1.465 [95% CI, 1.282-1.655]; P<0.0001). CONCLUSIONS: Plasma corin levels at baseline is a valuable predictor of AF recurrence after CA, independent of established conventional risk factors. Risk stratification before ablation for AF may be useful in selecting treatment regimens for patients.

Analyzing the correlation between quinolone-resistant Escherichia coli resistance rates and climate factors: A comprehensive analysis across 31 Chinese provinces.

BACKGROUND: The increasing problem of bacterial resistance, particularly with quinolone-resistant Escherichia coli (QnR eco) poses a serious global health issue. METHODS: We collected data on QnR eco resistance rates and detection frequencies from 2014 to 2021 via the China Antimicrobial Resistance Surveillance System, complemented by meteorological and socioeconomic data from the China Statistical Yearbook and the China Meteorological Data Service Centre (CMDC). Comprehensive nonparametric testing and multivariate regression models were used in the analysis. RESULT: Our analysis revealed significant regional differences in QnR eco resistance and detection rates across China. Along the Hu Huanyong Line, resistance rates varied markedly: 49.35 in the northwest, 54.40 on the line, and 52.30 in the southeast (P = 0.001). Detection rates also showed significant geographical variation, with notable differences between regions (P < 0.001). Climate types influenced these rates, with significant variability observed across different climates (P < 0.001). Our predictive model for resistance rates, integrating climate and healthcare factors, explained 64.1% of the variance (adjusted R-squared = 0.641). For detection rates, the model accounted for 19.2% of the variance, highlighting the impact of environmental and healthcare influences. CONCLUSION: The study found higher resistance rates in warmer, monsoon climates and areas with more public health facilities, but lower rates in cooler, mountainous, or continental climates with more rainfall. This highlights the strong impact of climate on antibiotic resistance. Meanwhile, the predictive model effectively forecasts these resistance rates using China's diverse climate data. This is crucial for public health strategies and helps policymakers and healthcare practitioners tailor their approaches to antibiotic resistance based on local environmental conditions. These insights emphasize the importance of considering regional climates in managing antibiotic resistance.

Comparative effectiveness of glycyrrhizic acid preparations aimed at improving liver function of patients with chronic hepatitis B: A network meta-analysis of 53 randomized controlled trials.

BACKGROUND AND OBJECTIVES: Entecavir (ETV) has disadvantages, such as poor improvement in liver function, during the treatment of Chronic hepatitis B (CHB). Thus ETV is often used in clinical therapy with glycyrrhizic acid (GA) preparations. However, due to the lack of reliable and direct clinical studies, it remains controversial whether glycyrrhizic acid preparations have the best efficacy in CHB. Therefore, we aimed to compare and rank the different GA preparations in the treatment of CHB using network meta-analysis (NMA). METHODS: We systematically searched MEDLINE, EMBASE, Cochrane Library, Web of Science, China national knowledge internet (CNKI), Wanfang, VIP, and SinoMed databases as of August 4, 2022. Literature was screened according to predefined inclusion and exclusion criteria to extract meaningful information. A Bayesian approach was used for random effects model network meta-analysis, and Stata 17 software was used for data analysis. RESULTS: From 1074 papers, we included 53 relevant randomized clinical trials (RCTs). For the primary outcome, we used the overall effective rate in assessing the effectiveness of treatment for CHB (31 RCTs including 3007 patients): CGI, CGT, DGC and MgIGI significantly reduced the incidence of overall response compared to controls (RRs range from 1.16 to 1.24); SUCRA results showed that MgIGI was the best (SUCRA 0.923). In terms of secondary outcomes, we assessed the effect of treatment for CHB according to the level of reduction in ALT and AST: for ALT (37 RCTs including 3752 patients), CGI, CGT, DGC, DGI and MgIGI significantly improved liver function index compared to controls (MD range from 14.65 to 20.41); SUCRA results showed that CGI was the best (SUCRA 0.87); for AST, GI, CGT, DGC, DGI and MgIGI significantly improved liver function index compared to the control group (MD range from 17.46 to 24.42); SUCRA results showed that MgIGI was the best (SUCRA 0.871). CONCLUSION: In this study, we verified that the combination of GA and Entecavir is more effective than entecavir monotherapy in the treatment of hepatitis B. MgIGI and CGI showed clinically significant effects on liver function recovery compared with other GA preparations. MgIGI appeared to be the best choice among all GA preparations for the treatment of CHB. Our study provides some references for the treatment of CHB.

Tumor Lysis Syndrome Associated with Monoclonal Antibodies in Patients with Multiple Myeloma: A Pharmacovigilance Study Based on the FAERS Database.

Although some tumor lysis syndrome (TLS) cases have been reported with patients with multiple myeloma (MM) taking monoclonal antibodies (mAbs), the association between TLS and mAbs remains mostly unknown. We aim to investigate the association between TLS and mAbs and describe clinical features. We conducted a disproportionality analysis to investigate the link between mAbs and TLS by excluding known confounders and compared with other anticancer drugs. The association between mAbs and TLS was evaluated using information component (IC). Drug-drug interaction signals were calculated based on the Ω shrinkage measure. Parametric distribution with the goodness-of-fit test was used for the reported time-to-onset analysis. From 2016 Q1, to 2022 Q4, a total of 274 TLS with mAbs were reported in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. There were 27% of patients with TLS with mAbs who died and 20.1% occurred a life-threatening situation. Daratumumab, elotuzumab, and belantamab mafodotin presented a robust disproportionate signal of TLS after excluding known confounders (IC025 > 0). Daratumumab had the highest disproportionate signal of TLS among all anticancer drugs for MM. Reported time-to-onset analysis showed the median days for TLS with daratumumab, isatuximab, elotuzumab, and belantamab mafodotin were 1.5, 14.5, 5.5, and 5.5 days, respectively. The drug-drug interaction analysis showed the co-administration of drugs known to increase urate, induce hyperkalemia, or hypocalcemia elevated the reporting frequency for TLS with mAbs (Ω025 > 0). Our postmarketing pharmacovigilance analysis detected the reporting association of TLS and mAbs in patients with MM. Additional studies with robust epidemiological study designs that can validate these findings are warranted.

Pneumocystis jirovecii pneumonia associated with immune checkpoint inhibitors: A systematic literature review of published case reports and disproportionality analysis based on the FAERS database.

Background: Pneumocystis jirovecii pneumonia (PJP) has been reported with ICIs but limited to case reports. The clinical features of PJP with ICIs remain mostly unknown. This study aims to investigate the association of PJP with ICIs and describe clinical features. Methods: Reports of PJP recorded in FAERS (January 2004-December 2022) were identified through the preferred term "Pneumocystis jirovecii pneumonia". Demographic and clinical features were described, and disproportionality signals were assessed through the Reporting Odds Ratio (ROR) and Information Component (IC), using traditional chemotherapy and targeted therapy as comparators, and adjusting signals by excluding contaminant immunosuppressive drugs and pre-existing diseases. A systematic literature review was conducted to describe clinical features of published PJP reports with ICIs. Bradford Hill criteria was adopted for global assessment of the evidence. Results: We identified 677 reports of PJP associated with ICIs, in which 300 (44.3%) PJP cases with fatal outcome. Nivolumab (IC025 2.05), pembrolizumab (IC025 1.88), ipilimumab (IC025 1.43), atezolizumab (IC025 0.36), durvalumab (IC025 1.65), nivolumab plus ipilimumab (IC025 1.59) have significant signals compared to other drugs in FAERS database. After excluding pre-existing diseases and immunosuppressive agents which may increase susceptibility of PJP, the signals for PJP associated with nivolumab, pembrolizumab, durvalumab, nivolumab plus ipilimumab remained robust (IC025 > 0). When compared to other anticancer regimens, although all ICIs showed a lower disproportionate signal for PJP than chemotherapy, nivolumab (IC025 0.33, p < 0.001), pembrolizumab (IC025 0.16, p < 0.001), both PD-1 inhibitors, presented a higher signal for PJP than targeted therapy. Male gender (IC025 0.26, p < 0.001) and age >65 years (IC025 0.38, p < 0.001) were predominant in PJP cases associated with across all ICIs. In literature, 15 PJP cases associated with ICIs were reported in 10 published case reports. 12 of 15 (80.0%) of cases received PD-1 inhibitors before PJP was diagnosed. Conclusion: By the combined analysis of post-marketing data from FAERS and published case reports, we identified ICIs may be associated with PJP, especially in males aged >65years. After accounting for confounders, PD-1 inhibitors emerged with a robust disproportionality signal when compared to PD-L1/CTLA-4 inhibitors as well as targeted therapy. Further research is warranted to validate our findings.

Clinical pharmacy undergraduate education in China: a comparative analysis based on ten universities' training programs.

BACKGROUND: In recent years, the scale of personnel training for clinical pharmacy professionals in China has expanded increasingly, however, the shortage of clinical pharmacists is still prominent. In 2018, the Ministry of Education of China released national standards for the teaching quality of undergraduate majors at regular colleges and universities, which has developed a core policy for undergraduate clinical pharmacy training. To explore the training methods for clinical pharmacy professionals in China and to promote the healthy and sustainable development of the clinical pharmacy education system. This study comparatively analyzed the training programs for clinical pharmacy undergraduates in China's ten universities, discussed training programs suitable for clinical pharmacy professionals in China. METHODS: The clinical pharmacy education programs in these ten universities were obtained through official school websites or by interviewing relevant people, and then compared and analyzed. RESULTS: The school with the largest number of courses and the most class hours in general courses is University A1 (34 courses, 1316 class hours), and the school with the most credits is University B1 (75.5 credits). The schools with the largest number of courses and the most class hours in the basic courses are University A1 (50 courses, 1997 class hours), and the schools with the most credits are University B3 and University B1 (105.5 credits). The schools with the largest number of courses in the core courses are University C1 (23 courses), and the school with the most credits and class hours is University B2 (51 credits, 914 class hours). The school with the most class hours in practical teaching is University B6 (1406 class hours), and the schools with the longest internship time are University A1 and University B6 (52 weeks). CONCLUSIONS: There was substantial variation in programs. There remains a gap between the existing educational model and clinical training in pharmacy in China and developed countries. China should explore the most appropriate method for undergraduate education in clinical pharmacy based on studying foreign excellent educational models and the experience of China.

Enhancing voriconazole therapy in liver dysfunction: exploring administration schemes and predictive factors for trough concentration and efficacy.

Introduction: The application of voriconazole in patients with liver dysfunction lacks pharmacokinetic data. In previous study, we proposed to develop voriconazole dosing regimens for these patients according to their total bilirubin, but the regimens are based on Monte Carlo simulation and has not been further verified in clinical practice. Besides, there are few reported factors that significantly affect the efficacy of voriconazole. Methods: We collected the information of patients with liver dysfunction hospitalized in our hospital from January 2018 to May 2022 retrospectively, including their baseline information and laboratory data. We mainly evaluated the efficacy of voriconazole and the target attainment of voriconazole trough concentration. Results: A total of 157 patients with liver dysfunction were included, from whom 145 initial and 139 final voriconazole trough concentrations were measured. 60.5% (95/157) of patients experienced the adjustment of dose or frequency. The initial voriconazole trough concentrations were significantly higher than the final (mean, 4.47 versus 3.90 µg/mL, p = 0.0297). Furthermore, daily dose, direct bilirubin, lymphocyte counts and percentage, platelet, blood urea nitrogen and creatinine seven covariates were identified as the factors significantly affect the voriconazole trough concentration. Binary logistic regression analysis revealed that the lymphocyte percentage significantly affected the efficacy of voriconazole (OR 1.138, 95% CI 1.016-1.273), which was further validated by the receiver operating characteristic curve. Conclusion: The significant variation in voriconazole trough concentrations observed in patients with liver dysfunction necessitates caution when prescribing this drug. Clinicians should consider the identified factors, particularly lymphocyte percentage, when dosing voriconazole in this population.

The Effect of Voriconazole on Tacrolimus in Kidney Transplantation Recipients: A Real-World Study.

Tacrolimus is an immunosuppressant with a narrow therapeutic window. Tacrolimus exposure increased significantly during voriconazole co-therapy. The magnitude of this interaction is highly variable, but it is hard to predict quantitatively. We conducted a study on 91 kidney transplantation recipients with voriconazole co-therapy. Furthermore, 1701 tacrolimus concentration data were collected. Standard concentration adjusted by tacrolimus daily dose (C/D) and weight-adjusted standard concentration (CDW) increased to 6 times higher during voriconazole co-therapy. C/D and CDW increased with voriconazole concentration. Patients with the genotype of CYP3A5 *3/*3 and CYP2C19 *2/*2 or *2/*3 were more variable at the same voriconazole concentration level. The final prediction model could explain 54.27% of the variation in C/D and 51.11% of the variation in CDW. In conclusion, voriconazole was the main factor causing C/D and CDW variation, and the effect intensity should be quantitative by its concentration. Kidney transplant recipients with CYP3A5 genotype of *3/*3 and CYP2C19 genotype of *2/*2 and *2/*3 should be given more attention during voriconazole co-therapy. The prediction model established in this study may help to reduce the occurrence of rejection.

Do antibody-drug conjugates increase the risk of sepsis in cancer patients? A pharmacovigilance study.

Introduction: Antibody-drug conjugates (ADCs) produce unparalleled efficacy in refractory neoplasms but can also lead to serious toxicities. Although ADC-related sepsis has been reported, the clinical features are not well characterized in real-world studies. Objective: The aim of this study was to identify the association between ADCs and sepsis using FAERS data and uncover the clinical characteristics of ADC-related sepsis. Methods: We performed disproportionality analysis using FAERS data and compared rates of sepsis in cancer patients receiving ADCs vs. other regimens. Associations between ADCs and sepsis were assessed using reporting odds ratios (RORs) and information component (IC). For each treatment group, we detected drug interaction signals, and conducted subgroup analyses (age, gender, and regimens) and sensitivity analyses. Results: A total of 24,618 cases were reported with ADCs between Q1, 2004 and Q3, 2021. Sepsis, septic shock, multiple organ dysfunction syndrome, and other sepsis-related toxicities were significantly associated with ADCs than other drugs in this database. Sepsis and multiple organ dysfunction syndrome have the highest safety concerns with ADCs compared with other anticancer monotherapies. Gemtuzumab ozogamicin and inotuzumab ozogamicin showed increased safety risks than other ADCs. For the top nine ADC-related sepsis, males showed higher sepsis safety concern than females (p <0.001); however, age did not exert influence on the risk of sepsis. We identified that 973 of 2,441 (39.9%) cases had acute myeloid leukemia (AML), and 766 of 2613 (29.3%) cases on ADCs died during therapy. Time-to-onset analysis indicated ADC-related sepsis is prone to occur within a month after administration. Co-administration of ADCs with colony-stimulating factors, proton pump inhibitors, H2-receptor antagonists, or CYP3A4/5 inhibitors showed to synergistically increase the risk of sepsis-related toxicities. Conclusion: Antibody-drug conjugates may increase the risk of sepsis in cancer patients, leading to high mortality. Further studies are warranted to characterize the underlying mechanisms and design preventive measures for ADC-related sepsis.

Voriconazole therapeutic drug monitoring and hepatotoxicity in critically ill patients: A nationwide multi-centre retrospective study.

OBJECTIVES: To characterize trough concentrations (Cmin) of voriconazole and associated hepatotoxicity, and to determine predictors of hepatotoxicity and identify high-risk groups in critically ill patients. METHODS: This was a nationwide, multi-centre, retrospective study. Cmin and hepatotoxicity were studied from 2015 to 2020 in 363 critically ill patients who received voriconazole treatment. Logistic regression and classification and regression tree (CART) models were used to identify high-risk patients. RESULTS: Large interindividual variability was observed in initial voriconazole Cmin and concentrations ranged from 0.1 mg/L to 18.72 mg/L. Voriconazole-related grade ≥2 hepatotoxicity developed in 101 patients, including 48 patients with grade ≥3 hepatotoxicity. The median time to hepatotoxicity was 3 days (range 1-24 days), and 83.2% of cases of hepatotoxicity occurred within 7 days of voriconazole initiation. Voriconazole Cmin was significantly associated with hepatotoxicity. The CART model showed that significant predictors of grade ≥2 hepatotoxicity were Cmin >3.42 mg/L, concomitant use of trimethoprim-sulfamethoxazole or tigecycline, and septic shock. The model predicted that the incidence of grade ≥2 hepatotoxicity among these high-risk patients was 48.3-63.4%. Significant predictors of grade ≥3 hepatotoxicity were Cmin >6.87 mg/L, concomitant use of at least three hepatotoxic drugs, and septic shock; the predictive incidence among these high-risk patients was 22.7-36.8%. CONCLUSION: Higher voriconazole Cmin, septic shock and concomitant use of hepatotoxic drugs were the strongest predictors of hepatotoxicity. Plasma concentrations of voriconazole should be monitored early (as soon as steady state is achieved) to avoid hepatotoxicity.

Therapeutic drug monitoring practices of anti-infectives: An Asia-wide cross-sectional survey.

Objectives: The current practice of therapeutic drug monitoring (TDM) in Asia is poorly documented. Our aim was to capture and describe TDM services delivered in hospitals across Asia, including aspects such as assay availability, interpretation of results and clinical decision-making. Methods: An online survey about anti-infective TDM practices, available in English and involving 50 questions, was promoted to people involved in TDM in Asia. The survey was open for responses from September to November 2021. Results: Of 207 responses from participants working in 14 Asian countries, 150 responses from 10 countries could be included. TDM services are available for many anti-infectives, providing assays based on chromatographic assays (100.0%) or immunoassays (39.3%). Clinicians (82.6%) and pharmacists (86.8%) were responsible for ordering and interpreting TDM. Most services provided reference targets and dose recommendations. Interpretative support was available to a varying degree. Assay results were available and clinical decision-making could be completed within 24 h in most hospitals (87.9% and 88.9% respectively). As the turnaround time of assay results decreased, the proportion of clinical decision-making completed within 8 h increased. Barriers to implementation of TDM included lack of funding or equipment (71.1%), lack of clinician interest or cooperation (47.0%), and lack of expertise (42.3%). Lack of expertise was the primary barrier for using precision dosing software (50.5%). Conclusion: There are significant differences and challenges in the development and practice of anti-infective TDM in Asian countries.

C/MIC > 4: A Potential Instrument to Predict the Efficacy of Meropenem

This prospective study aimed to explore the determinants of meropenem trough concentration (Ctrough) in patients with bacterial pneumonia and to investigate the association between its concentration and efficacy. From January 2019 to December 2019, patients with pulmonary infections were prospectively enrolled from the intensive care unit. Factors affecting the meropenem trough concentration were analyzed, and a multiple linear regression model was constructed. Logistic regression analyses were used to investigate the relationship between Ctrough and clinical efficacy. A total of 64 patients were enrolled, in whom 210 meropenem concentrations were measured. Of the total, 60.9% (39/64) were considered clinically successful after treatment. Ctrough may increase with increased blood urea nitrogen, albumin, and concomitant antifungal use. By contrast, concentration may decrease with increased endogenous creatinine clearance rate. Six variables, including Ctrough/minimum inhibitory concentration (MIC) > 4, were associated with the efficacy of meropenem. There was an independent correlation between Ctrough/MIC > 4 and efficacy after fully adjusting for confounding factors. Based upon renal function indexes, it is possible to predict changes in meropenem concentration and adjust the dosage precisely and individually. Ctrough/MIC > 4 is a potential instrument to predict successful treatment with meropenem.

Association of Pulmonary Sepsis and Immune Checkpoint Inhibitors: A Pharmacovigilance Study.

Background: Although some sepsis cases were reported with immune checkpoint inhibitors (ICIs) in clinical trials, the link between pulmonary sepsis and ICIs remains mostly unknown. We aim to investigate the association between pulmonary sepsis and ICIs, and to describe the clinical features. Methods: A disproportionality analysis was performed using FAERS data and compared rates of pulmonary sepsis in cancer patients receiving ICIs vs. other drug regimens (such as chemotherapy and targeted therapy). Associations between ICIs and sepsis were assessed using reporting odds ratios (ROR) and information component (IC). We also detected drug interaction signals based on the Ω shrinkage measure. Age and gender distribution were compared between pulmonary sepsis and all adverse events associated with ICIs. Results: We identified 120 reports of pulmonary sepsis associated with ICIs between Q1, 2011 to Q3, 2021. A total of 82 of 120 (68.3%) patients on ICIs suffered from pulmonary sepsis and progressed to death. In addition, there is no significant difference in age and gender in the occurrence of pulmonary sepsis in cancer patients on ICIs. Overall ICIs, nivolumab, and atezolizumab still have a significant signal of pulmonary sepsis (ROR025 > 1, IC025 > 0, p < 0.001) compared with targeted therapy (such as tyrosine kinase inhibitors) or chemotherapy. Co-administration of ICIs and glucocorticoids or proton pump inhibitors synergistically increased the risk of pulmonary sepsis (Ω025 > 0). Conclusions: Our study suggested ICIs, especially nivolumab and atezolizumab, tended to increase the risk of pulmonary sepsis more than other anticancer regimens. Clinicians should be vigilant in the prevention and management of pulmonary sepsis during ICIs therapy.

Does Prolonged Infusion Time Really Improve the Efficacy of Meropenem Therapy? A Prospective Study in Critically Ill Patients.

INTRODUCTION: Meropenem is a carbapenem antibiotic, which has demonstrated excellent antimicrobial activity against gram-negative clinical isolates. It is also commonly used in critically ill patients. This study aimed to determine the pharmacokinetics/pharmacodynamics of meropenem in critically ill patients and whether prolonged injection duration is really beneficial to meropenem therapy. METHODS: We included 209 samples in 64 patients in this prospective study. PPK analysis and Monte Carlo dosing simulations were developed using Phoenix. RESULTS: A two-compartment model described the data adequately. Clearance (CL), volume (V), clearance of peripheral compartment (CL2), and volume of peripheral compartment (V2) were 6.15 l/h, 2.83 l/h, 17.40 l, and 17.48 l, respectively. Creatinine clearance and uric acid were significant covariates. Patients with creatinine clearance ≤ 60 ml/min and uric acid > 400 µmol/l could achieve the target > 90% under the minimum inhibitory concentration (MIC) of 8 mg/l, even with the administration dose of 500 mg/8 h with a 2-h infusion. Prolonging the infusion time significantly improved the therapeutic effect when MIC < 4. However, for the pharmacodynamic (PD) effects of 100% fT > MIC and 100% fT > 4 MIC, no significant statistical difference was observed in critically ill patients. CONCLUSIONS: Critically ill patients with lower creatinine clearance and higher uric acid levels tended to need a lower dosage of meropenem. Prolonged infusion time was not always beneficial for those who needed a higher therapeutic target (100% fT > MIC, 100% fT > 4 MIC) or with MIC > 4 mg/l. Increasing dose or alternative therapeutic strategies may be required for critically ill patients with drug-resistant or severe infections. The study is of great significance to guide the rational use of meropenem in critically ill patients. TRIAL REGISTRATION: The trial was registered in the China Clinical Trial (ChiCTR1900020672). Registered on 12 January 2019.

Meropenem is commonly used empirically or targeted in critically ill patients for bacterial infection. Many studies have reported that prolonged infusion time can improve the efficacy of meropenem therapy. However, we are skeptical about that. Meanwhile, prolonged injections can sometimes cause mobility problems for patients. A quantitative method is used to evaluate meropenem use. It is called the population pharmacokinetic model or pharmacodynamic study. Using this method, we found two significant influencing factors of meropenem metabolism: creatinine clearance and uric acid level. It is likely that patients with a lower level of creatinine clearance and a high uric acid level tend to require lower dosages of meropenem. As for the effect of infusion time, Monte Carlo simulation was used, which can do 3000 simulations on an individual. The result was complex. We found infusion time was beneficial only when bacteria were sensitive to meropenem. The evidence suggests that prolonged injection duration sometimes does not significantly improve the outcome of antimicrobial therapy.

Factors Affecting Voriconazole Trough Concentration and Optimal Maintenance Voriconazole Dose in Chinese Children.

Voriconazole is a triazole antifungal agent commonly used for the treatment and prevention of invasive aspergillosis (IA). However, the study of voriconazole's use in children is limited. The present study was performed to explore maintenance dose to optimize voriconazole dosage in children and the factors affecting voriconazole trough concentration. This is a non-interventional retrospective clinical study conducted from 1 January 2016 to 31 December 2020. The study finally included 94 children with 145 voriconazole trough concentrations. The probability of achieving a targeted concentration of 1.0-5.5 µg/mL with empiric dosing increased from 43 (45.3%) to 78 (53.8%) after the TDM-guided adjustment. To achieve targeted concentration, the overall target maintenance dose for the age group of less than 2, 2 to 6, 6 to 12, and 12 to 18 years old was approximately 5.71, 6.67, 5.08 and 3.31 mg·kg-1/12 h, respectively (p < 0.001). Final multivariate analysis found that weight (p = 0.019), dose before sampling (p < 0.001), direct bilirubin (p < 0.001), urea nitrogen (p = 0.038) and phenotypes of CYP2C19 were influencing factors of voriconazole trough concentration. These factors can explain 36.2% of the variability in voriconazole trough concentration. Conclusion: In pediatric patients, voriconazole maintenance doses under the target concentration tend to be lower than the drug label recommended, but this still needs to be further studied. Age, body weight, dose, direct bilirubin, urea nitrogen and phenotypes of CYP2C19 were found to be influencing factors of voriconazole concentration in Chinese children. The influence of these factors should be taken into consideration during voriconazole use.

A Large Sample Retrospective Study on the Distinction of Voriconazole Concentration in Asian Patients from Different Clinical Departments.

Voriconazole (VRZ) is widely used to prevent and treat invasive fungal infections; however, there are a few studies examining the variability and influencing the factors of VRZ plasma concentrations across different clinical departments. This study aimed to evaluate distinction of VRZ concentrations in different clinical departments and provide a reference for its reasonable use. From 1 May 2014 to 31 December 2020, VRZ standard rates and factors affecting the VRZ trough concentration were analyzed, and a multiple linear regression model was constructed. The standard rates of VRZ in most departments were above 60%. A total of 676 patients with 1212 VRZ trough concentrations using a dosing regimen of 200 mg q12h from seven departments were enrolled in the correlation analysis. The concentration distribution varied significantly among different departments (p < 0.001). Fifteen factors, including department, CYP2C19 phenotype, and gender, correlated with VRZ concentration. A multiple linear regression model was established as follows: VRZ trough concentration = 5.195 + 0.049 × age + 0.007 × alanine aminotransferase + 0.010 × total bilirubin - 0.100 × albumin - 0.004 × gamma-glutamyl transferase. According to these indexes, we can predict possible changes in VRZ trough concentration and adjust its dosage precisely and individually.

Predictors of Voriconazole Trough Concentrations in Patients with Child-Pugh Class C Cirrhosis: A Prospective Study.

This prospective observational study aimed to clinically describe voriconazole administrations and trough concentrations in patients with Child-Pugh class C and to investigate the variability of trough concentration. A total of 144 voriconazole trough concentrations from 43 Child-Pugh class C patients were analyzed. The majority of patients (62.8%) received adjustments. The repeated measured trough concentration was higher than the first and final ones generally (median, 4.33 vs. 2.99, 3.90 mg/L). Eight patients with ideal initial concentrations later got supratherapeutic with no adjusted daily dose, implying accumulation. There was a significant difference in concentrations among the six groups by daily dose (p = 0.006). The bivariate correlation analysis showed that sex, CYP2C19 genotyping, daily dose, prothrombin time activity, international normalized ratio, platelet, and Model for end-stage liver disease score were significant factors for concentration. Subsequently, the first four factors mentioned above entered into a stepwise multiple linear regression model (variance inflation factor <5), implying that CYP2C19 testing makes sense for precision medicine of Child-Pugh class C cirrhosis patients. The equation fits well and explains the 34.8% variety of concentrations (R2 = 0.348). In conclusion, it needs more cautious administration clinically due to no recommendation for Child-Pugh class C patients in the medication label. The adjustment of the administration regimen should be mainly based on the results of repeated therapeutic drug monitoring.